Endogenous opiate peptides (enkephalins and dynorphin) within the dorsal (caudate-putamen nuclei, CPN) and ventral (nucleus accumbens septi) striatum have been implicated in motor and sensory responses to peripheral stimuli and in the rewarding properties of several drugs of abuse. These are most likely mediated by interactions between neurons containing endogenous opiates and transmitters in other neurons or afferents in compartmentally specific divisions of the dorsal and ventral striatum. In this competitive renewal, three studies are proposed that continue to investigate the cellular basis for functional interactions involving endogenous striatal opiates. Studies I and II will examine compartmentally specific subregions of dorsal and ventral striatum of normal adult rats using primarily combined immunogold-silver and immunoperoxidase labeling of two antibodies in single sections by electron microscopy (EM). Study I seeks to establish whether there is a cellular basis for functional interactions involving enkephalins and/or dynorphin and gamma-aminobutyric acid (GABA) or acetylcholine, two prominent transmitters in spiny and aspiny neurons. Study II seeks to determine (1) whether cortical or monoaminergic afferents terminate on neurons containing specific opiates, and/or (2) whether the neurons containing these opiates have other types of axonal associations with cortical or monoaminergic afferents that could mediate presynaptic modulation or dual regulation of common target neurons. Study III will use quantitative light microscopic immunocytochemical and in situ hybridization methods and morphometric EM-immunocytochemical analysis. The goal of this study is to determine whether neurons and/or astrocytes containing endogenous opiates, nerve growth factor, or S-100 protein show changes consistent with specific roles in plasticity of adult striatal cholinergic neurons or other afferents following neonatal neurotoxic lesions of dopaminergic neurons. The results from these three studies will provide basic science information relative to understanding how excitatory cortical afferents and monoaminergic afferents to the striatum modulate local circuits between neurons containing endogenous opiates and related transmitters in normal adult animals and in animals showing striatal compensation for neonatal dopamine depletion. The findings have implications for understanding mechanisms important for drug abuse, forebrain analgesia, and several motor and sensory disorders in humans.